Question 17

College Answer

Description of sequential events from axon conduction to detail at the neuromuscular junction was required. Well-constructed answers defined neuromuscular transmission, elucidated the structure of the neuromuscular junction (best done with a detailed diagram), described the central importance of acetylcholine, including synthesis, storage, receptors, and degradation. An ideal answer also described both pre-synaptic (e.g. voltage-gated calcium channels, exocytosis of vesicles) and post-synaptic events (acetylcholine receptors, end plate potentials, and the events that lead to excitation-contraction coupling in skeletal muscle).

Discussion

Notably, the question asked for an explanation of the physiology, and the unwary reader may interpret this as asking only for the physiology of NMJ neurotransmission, but from the comments we can see that the question was interested in the structure as much as the function.  The candidates are again warned to read between the lines to scry the content of the examiners' minds.

• Definition
  • The neuromuscular junction is a specialised synapse for the transmission of a signal from the motor nerve terminal to a postsynaptic region on the muscle fibre.
• Structure:
  • Presynaptic membrane
    • Neuronal membrane featuring voltage-gated calcium channels and docked acetylcholine-filled vesicles that are ready for immediate exocytosis
    • Acetylcholine is synthesised from choline and acetate by choline acetyltransferase, and sequestered in vesicles by low pH
  • Synaptic gap
    • Narrow (~70nm) space filled with basal lamina proteins and acetylcholinesterase
  • Postsynaptic membrane (motor endplate)
    • Deeply furrowed membrane, 8-10 times the surface area of the presynaptic membrane
    • Covered in nicotinic acetylcholine receptors (10,000 per μm²). 
• Function:
  • An action potential arrives via the motor axon (a 100-120 m/s)
  • At the presynaptic membrane, voltage-gated calcium channels open in response to membrane depolarisation
  • The intracellular calcium activates SNARE proteins which open acetylcholine vesicles
  • Acetylcholine spills into the synapse (abundantly, with a safety factor of 3-5 times the minimum amount required to achieve endplate depolarisation)
  • It is then rapidly (within 1ms) hydrolysed by a high-affinity acetylcholinesterase
  • During its synaptic dwell time, acetylcholine activates nicotinic acetylcholine receptors
  • These are pentameric ligand-gated transmembrane cation channels that mediate sodium entry into the cell
  • The sodium influx depolarises the membrane and activates nearby voltage-gated sodium channels, creating the endplate action potential
  • This action potential then propagates along the muscle fibre sarcolemma, notably delving into T tubules that penetrate deep into the myocyte where they activate calcium channels necessary for excitation-contraction coupling.

King, John M., and Jennifer M. Hunter. "Physiology of the neuromuscular junction." Bja Cepd Reviews 2.5 (2002): 129-133.

Ruff, Robert L. "Neurophysiology of the neuromuscular junction: overview." Annals of the New York Academy of Sciences 998.1 (2003): 1-10.

Engel, Andrew G. "The neuromuscular junction." Handbook of clinical neurology 91 (2008): 103-148.

Pavelka, Margit, and Jürgen Roth. "Neuromuscular Junction." Functional Ultrastructure. Springer, Vienna, 2010. 304-305.

Hong, Ivan HK, and Sarah J. Etherington. "Neuromuscular junction." eLS (2011).